Synthesis of Indole‐Derived Allocolchicine Congeners through Pd‐Catalyzed Intramolecular C‐H Arylation Reaction

Abstract

The synthesis of several new heterocyclic structural analogs of the natural antimitotic agent allocolchicine is reported. As a key step an intramolecular Pd‐catalyzed C–H arylation reaction was used to close the seven‐membered ring fused with two electron‐rich aryl fragments. The stereostructure of the target compounds was determined by X‐ray crystal analysis. The primary biological assessment of the synthesized compounds was carried out on human lymphoma cells. Several allocolchicinoids were determined to possess antiproliferative and apoptosis‐inducing activity in the micromolar concentration range.

Influence of Aromatic Residues on the Material Characteristics of Aβ Amyloid Protofibrils at the Atomic Scale

“…An intramolecular CH activation event at the C‐3 position was employed in the synthesis of indole‐based allocolchicine derivatives, described by the groups of Schmalz and Fedorov and co‐workers 105. Two slightly divergent methods were employed depending on the substituent on the N‐1 ring atom to afford the corresponding annulated indoles in good yields (Scheme ).…”

Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

“…34 In 2009, Pieters and co-workers reported that compound 40 and its hydroiodide 39 were very active against Plasmodium falciparum (IC < 1 μM for 40), but were also very highly cytotoxic and exhibited low selectivity. 30 In 2014, Schmalz, Federov and co-workers 35 synthesized some indole-derived structural analogues of the natural antimitotic allocolchicine (41) ( Figure 6). 36 They used a reaction sequence in which the first step was a palladium-catalyzed intramolecular direct arylation of 3-(2′-iodo-3′,4′,5′trimethoxyphenyl)-1-(1′′-methyl-1H-indol-2′′-yl)propan-1-one (42) (Scheme 10).…”

“…36 They used a reaction sequence in which the first step was a palladium-catalyzed intramolecular direct arylation of 3-(2′-iodo-3′,4′,5′trimethoxyphenyl)-1-(1′′-methyl-1H-indol-2′′-yl)propan-1-one (42) (Scheme 10). 35…”

“…furnished 7H-indolo [2,3-c]quinolone (35) in 45% yield together with compound 36 in 4% yield. Applying the hypothesis of an electrophilic palladation on the quinoline system as the mechanistic key step, the authors attributed the preferential C4-H activation to the higher number of resonance structures able to preserve the aromaticity of the benzene moiety, along with a larger electron density on C4 than on C2.…”

Synthesis of Diverse 6‐Oxa‐allocolchicinoids by a Suzuki–Miyaura Coupling, Acid‐Catalyzed Intramolecular Transacetali­zation Strategy

“…This included a proliferation assay to determine cell concentrations and viability by using a CASI cell counter and apoptosis assays for nuclear DNA fragmentation quantified by FACS flow cytometric determination. For a full description of the methods involved in the preliminary evaluation of the compounds, see the supporting information of ref 7e. For details of the synergism experiments between 16da and vincristine on vincristine‐resistant cell lines, please refer to the Supporting Information.…”